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SEQUOIA-HCM Trial

CardioNerds Journal Club is a monthly forum for CardioNerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the SEQUOIA-HCM Trial.

Table of contents for the The SEQUOIA-HCM Trial summary:

SEQUOIA HCM Trial CardioNerds CardsJC

Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy

Martin S. Maron, M.D., Ahmad Masri, M.D., Michael E. Nassif, M.D., Roberto Barriales-Villa, M.D., Ph.D., Michael Arad, M.D., Nuno Cardim, M.D., Ph.D., Lubna Choudhury, M.D., +26, for the SEQUOIA-HCM Investigators

https://www.nejm.org/doi/full/10.1056/NEJMoa2401424

Relevant Literature

Relevant Guidelines

2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy (HCM)

2023 ESC Guidelines for the management of cardiomyopathies: Developed by the task force on the management of cardiomyopathies of the European Society of Cardiology

Study Rational

HCM with LVOTO remains difficult to treat. Invasive therapies, under the umbrella term of septal reduction therapies (SRT), include surgical myectomy and percutaneous alcohol septal ablation. While they effectively relieve LVOT gradients and associated symptoms, they have associated risks and are done at a few high-volume centers. Conversely, historically utilized medications (beta blockers, non-dihydropyridine calcium channel blockers, and disopyramide) have suboptimal relief of LVOT gradients and symptoms.

Mavacamten, a cardiac myosin ATPase inhibitor, was approved by the FDA in 4/29/2022 based on the EXPLORER-HCM trial showing improvement in symptoms and exercise capacity. Aficamten has the same mechanism of action as mavacamten, with a few potential advantages:

  • shallow dose response relationship: smaller reductions in LVEF as dose is increased;
  • shorter half-life: steady state in 2 weeks (compared to 4-6 weeks with mavacamten);
  • does not interact with the cytochrome p450 system (no drug-drug interactions).

Objectives

The primary goal was to evaluate the efficacy and safety of aficamten in adult patients with symptomatic obstructive HCM.  The efficacy was assessed by changes in peak oxygen uptake during cardiopulmonary exercise testing and numerous secondary endpoints (see below). Safety was assessed by reporting adverse events during the study period.

 Details 
Trial Type International, double-blind, randomized, placebo-controlled trial involving 80 sites
Randomization Randomly assigned in a 1:1 ratio to receive aficamten or placebo
Dosage The starting dose of aficamten was 5 mg, with three subsequent opportunities (at weeks 2, 4, and 6) to increase the dose by 5-mg increments, to a maximum dose of 20 mg
Follow-up Patients were followed during the 24-week treatment period and during a 4-week washout period at the end of the trial.
Interim Analyses No interim analyses were performed

Enrollment Criteria

  • Patients between the ages of 18 and 85 years
  • Confirmed clinical diagnosis of HCM
  • Left ventricular wall thickness of at least 15 mm in the absence of pressure overload or other discernible causes
  • Left ventricular ejection fraction of at least 60%
  • Left ventricular outflow tract gradients of at least 30 mmHg at rest and at least 50 mmHg after the Valsalva maneuver
  • NYHA II-III
  • Decreased exercise capacity
  • Defined by a predicted peak oxygen uptake of 90% or less on the basis of age and sex

Outcomes

Primary end point: The change from baseline to week 24 in the peak oxygen uptake as assessed during cardiopulmonary exercise testing

Secondary end points:

  1. Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS):
    1. change from baseline -> week 24
    1. change from baseline -> week 12
  • NYHA functional class:
    • improvement from baseline of at least one class at week 24
    • improvement from baseline of at least one class at week 12
  • LVOT gradient after Valsalva:
    • change from baseline -> week 24
    • change from baseline -> week 12
    • decrease in gradient to < 30 mmHg after Valsalva at week 24
    • decrease in gradient to < 30 mmHg after Valsalva at week 12
  • Duration of eligibility for SRT during the 24-week treatment period among patients who were eligible for such therapy at baseline
    • eligibility defined by NYHA functional class III or IV disease and a LVOT tract gradient (at rest or after the Valsalva maneuver) of ≥50 mmHg
  • Total workload as assessed by cardiopulmonary exercise testing: change at week 24

Statistical Analysis

  1. The trial was designed with at least 90% power to detect the between-group difference in the change from baseline in the peak oxygen uptake at week 24 of 1.5 ml/kg of body weight/min, with a standard deviation of 3.5 ml/kg/min, at a two-sided type I error level of 0.05.
  2. The primary analysis tested the null hypothesis that there would be no between-group difference with respect to the primary end point in the full analysis set.
  3. To adjust for multiplicity, hierarchical testing was utilized. Only if the primary end point showed a significant treatment effect at a two-sided P value of less than 0.05, then the secondary end points would be tested sequentially at a two-sided level of 0.05.

Notable Baseline Characteristics

  • A total of 543 patients were screened for eligibility at 101 sites in 14 countries, of whom 282 underwent randomization and received aficamten or placebo.
  • The most common reasons for exclusion:
    • inadequately elevated LVOT gradients after the Valsalva maneuver;
    • not meeting cardiopulmonary exercise testing criteria.
  • Overall, the mean age was 59.1 years, 59.2% were men, and 79.1% identified as White.
  • 25% of patients had a family history of HCM, with 17.5% having a pathogenic sarcomeric variant.
  • Overall, the baseline mean resting LVOT gradient was 55 mmHg and mean LVOT gradient with Valsalva was 83 mmHg. The baseline mean left ventricular ejection fraction (LVEF) was 75%.
  • At screening, 61.3% of the patients were receiving beta-blockers, 28.7% were receiving calcium channel blockers, and 12.8% were receiving disopyramide.
  • At the end of the dose-escalation phase (week 8), 3.6%, 12.9%, 35.0%, and 48.6% of the patients assigned to the aficamten group were receiving aficamten at a dose of 5 mg, 10 mg, 15 mg, and 20 mg, respectively.
  • Most patients were NYHA Class II – 78.9%.
  • Intervention and placebo groups were comparable across baseline characteristics.

Primary Outcome

The primary endpoint, mean change from baseline to week 24 in peak VO2 uptake, for aficamten vs. placebo, was: 1.8 vs. 0.0 mL/kg/min, least square mean difference: 1.7 mL/kg/min (p < 0.0001).

Secondary Outcomes

  • Change in Kansas City Cardiomyopathy Questionnaire-clinical summary score (KCCQ-CSS) at week 24: 12 vs. 5 (p < 0.001)
  • LVOT gradient ≤30 mm Hg after Valsalva at week 24: 49.3% vs. 3.6% (p < 0.001)
  • Change in LVOT gradient at week 24: -47.6 vs. 1.8 mm Hg (p < 0.001)
  • Geometric mean proportional change in NTproBNP at week 24: 0.20 vs. 0.20 (p > 0.05)
  • Serious adverse events: 5.6% vs. 9.3%

Adverse Events

Serious adverse events were reported in 8 patients (5.6%) in the aficamten group and in 13 patients (9.3%) in the placebo group.

  • The number of patients who had at least one adverse event after the start of administration of aficamten or placebo was 105 (73.9%) in the aficamten group and 99 (70.7%) in the placebo group.
    • Atrial fibrillation: 2.8% vs. 2.9%
    • Ventricular fibrillation 0% vs. 0.7
    • Palpitations: 7.0% vs. 2.9%
    • Hypertension: 7.7% vs. 2.1%
  • At week 24, the LVEF in the aficamten group was modestly lower than that in the placebo group (least-squares mean difference, –4.8 percentage points; 95% CI, –6.3 to –3.2)
  • After the 4-week washout period, there was no marked difference between the groups in the LVEF (least-squares mean difference, –1 percentage points; 95% CI, –2 to 0).
  • A transient reduction of less than 50% in the LVEF occurred in 5 patients (3.5%) in the aficamten group and in 1 patient (0.7%) in the placebo group
  • 7 patients (4.9%) in the aficamten group underwent a per protocol dose reduction on the basis of the site echocardiographic evaluation.
  • None of the patients in the aficamten group with a LVEF of less than 50% had an interruption of treatment or an exacerbation of heart failure.

The trial was designed to estimate the treatment effects of early initiation and later initiation of DOACS and provide qualitative data to guide clinicians.

  • The study ultimately found that the incidence of compositive of stroke, systemic embolism, hemorrhage, or death at 30 days was estimated to be in the range from 2.8% points lower to 0.5% points higher (95% CI) with the early use of DOACS than with later use
  • Based on this, early treatment can be supported
  • Comparing the 90 day outcomes to the 30 day, there was not an excessive risk associated with early anticoagulation use within this period

Limitations & Considerations

  • This study excludes individuals who received therapeutic anticoagulation at baseline
  • Limited statistical power to explore the subgroups
  • Trial population was predominantly from European centers with a higher proportion of White participants
  • Those with parenchymal hemorrhage were excluded so these results on anticoagulation cannot be extrapolated to this group

The results of this trial indicate that aficamten at a dose of 5-20 mg daily improved exercise capacity as assessed by cardiopulmonary exercise testing over a 24-week treatment period compared with placebo among patients with symptomatic HCM, the majority of whom were already on background therapy. These results are very promising and another option to our armamentarium for HCM management. Due to it’s improved pharmacokinetic properties as compared to mavacamten, aficamten may allow more patients to be able to tolerate and utilize a myosin inhibitor. A future head to head comparison with mavacamten as well as understanding of cost-benefit of these drugs would be helpful for clinicians when they are deciding on the management of their HCM patients.

Indik JH, Wang A, Geske JB, et al. Mavacamten in Symptomatic Patients With Obstructive Hypertrophic Cardiomyopathy. J Am Coll Cardiol. 2022;79(16):1565-1575. doi: 10.1016/j.jacc.2022.02.024

Olivotto I, Oreziak A, Barriales-Villa R, et al. Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): a randomised, double-blind, placebo-controlled, phase 3 trial. The Lancet. 2020;396(10253):759-769. doi: 10.1016/S0140-6736(20)31792-X

Desai MY, Owens A, Geske JB, et al. Myosin Inhibition in Patients With Obstructive Hypertrophic Cardiomyopathy Referred for Septal Reduction Therapy. J Am Coll Cardiol. 2022;80(2):95-108. doi: 10.1016/j.jacc.2022.04.048

Maron MS, Masri A, Nassif ME, et al. Aficamten for Symptomatic Obstructive Hypertrophic Cardiomyopathy. N Engl J Med. 2024;390(20):1849-1861. doi: 10.1056/NEJMoa2401424

Ommen SR, Mital S, Burke MA, et al. 2020 AHA/ACC Guideline for the Diagnosis and Treatment of Patients With Hypertrophic Cardiomyopathy: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2020;142(25). doi: 10.1161/CIR.0000000000000937

Ommen SR, Ho CY, Asif IM, et al. 2024 AHA/ACC/AMSSM/HRS/PACES/SCMR Guideline for the Management of Hypertrophic Cardiomyopathy: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guideline. Circulation. 2024;149(23). doi: 10.1161/CIR.0000000000001250

Arbelo E, Protonotarios A, Gimeno JR, et al. 2023 ESC Guidelines for the management of cardiomyopathies. Eur Heart J. 2023;44(37):3503-3626. doi: 10.1093/eurheartj/ehad194

Summary By:

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Trial Tweets:

Dr. Apoorva Gangavelli, Internal Medicine Resident, Emory University

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